1. Synergistic therapeutic effect of combined PDGFR and SGK1 inhibition in metastasis-initiating cells of breast cancer
- Author
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Lu Yang, Xiaojia Huang, Ning Li, Yutian Zou, Xinhua Xie, Jian Li, Ling Rui Liu, Xiaoming Xie, Zhicheng Xue, and Hailin Tang
- Subjects
0301 basic medicine ,Lung Neoplasms ,Cell Survival ,Antineoplastic Agents ,Breast Neoplasms ,Mice, SCID ,Protein Serine-Threonine Kinases ,Ligands ,Benzoates ,Models, Biological ,Article ,Immediate-Early Proteins ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Mice, Inbred NOD ,Cancer stem cell ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Receptors, Platelet-Derived Growth Factor ,Neoplasm Metastasis ,Molecular Biology ,Protein kinase B ,Cell Proliferation ,biology ,business.industry ,Cancer ,Drug Synergism ,Cell Biology ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Primary tumor ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,Quinolines ,Cancer research ,biology.protein ,Benzimidazoles ,Female ,business ,Platelet-derived growth factor receptor - Abstract
Lack of insight into the identity of the cells that initiate metastasis hampers the development of antimetastatic therapies. Only a tiny fraction of tumor cells termed metastasis-initiating cells (MICs) are able to successfully seed metastases, causing recurrence and therapeutic resistance. Using metastasis models, we describe a subpopulation of MIC derivates from lung metastases that do not have proliferation advantages, express high levels of the PDGF receptors and EMT/stemness-related genes, and are unique in their ability to initiate metastasis. PDGF factors specifically boost the metastatic potential of MIC populations in a PDGFR-dependent manner. However, PDGFR inhibition preferentially suppresses lung metastases, but does not reduce the primary tumor burden. Thus, we found that PDGFR inhibition blocks AKT activation, whereas SGK1, which shares high-similarity kinase domain and overlap substrates with AKT overexpression remains active in MICs. SGK1 and PDGF signaling act in concert to promote metastatic formation, and SGK1 inhibition confers vulnerability to PDGFR inhibitors, also eliciting a powerful antitumor effect. In vivo, SGK1 inhibitors sensitize xenograft tumors to PDGFR-targeted therapies by reducing primary tumor growth and lung metastasis. Consequently, dual inhibition of PDGFR and SGK1 exhibited strong antitumor activities in established breast cancer cell lines in vitro and in vivo. Therefore, this approach not only provides insight into MIC transformation but also aids the design of improved therapeutic strategies for advanced breast cancer.
- Published
- 2020